The long- term objective of this research is to modify and improve the immunogenicity of the HIV-1 envelope protein in order to develop an efficacious HIV-1 vaccine. Infection with HIV-1 in the majority of people results in a chronic, active and progressive infection ultimately ending in death from opportunistic infections and/or cancer. Although a vigorous host response is elicited to the genetically unstable virus, the chronic active infection normally proceeds unchecked. The immune response is initially directed at limited epitopes on the viral envelope that are unusually immunodominant and ultimately non-protective. "Deceptive Imprinting," as it has become known, appears to have a decoying and short-circuiting effect on the immune system, and tends to prevent the immune system from directing its anti-viral activity toward more conserved and functional determinants involved in replication and/or pathogenesis. Recent research aimed at dampening or masking one of these immunodominant epitopes, V3, resulted in the development of a novel approach to shift the immune response to more conserved parts of the molecule. In these studies, a previously silent, second order series of immune responses, characterized by a broader degree of neutralization, were established. Additional hypervariable and immune thwarting epitopes have been identified in addition to the V3 domain. These occur in both the gpl20 and gp41 domains and are the focus of research in this proposal. Dampening these genetically variable and infection-enhancing epitopes will allow other more broadly protective epitopes to trigger the immune response. Thus, broadly neutralizing antibody and cell-mediated responses may be generated against primary HIV-1 isolates obtained from peripheral blood mononuclear cells (PBMCs) and macrophage cell types.